Abstract

Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.

(A) Schematic presentation of the experimental paradigm: ablation of the C-row of whiskers at P1 causes corresponding reorganization of barrel representations at P7 in contralateral hemisphere.(B Immunolabeling of thalamocortical afferents to the barrel cortex with an antibody against 5HT transporter. Left images show control barrel cortex. Right images are representative examples of lesion-induced plasticity following whisker follicle ablation in mice that were injected with saline (top), with GBP (middle). Bottom row are control (left) and lesioned (right) barrel cortices from a TSP1/2KO mouse. Arrows flank the C-row of barrels corresponding to lesioned whiskers. Brackets and dashed lines show the expansion of D-row barrels. Asterisks denote regions of abnormal lesion-induced plasticity.(C) Hematoxylin staining of the whisker pads from mice whose barrels are shown in (B) showing selective ablation of C row follicles.